Whitehall II is a longitudinal study set up in 1985 to investigate the determinants of the social gradient in coronary heart disease (CHD). We wished to test two hypotheses regarding the causes of the social gradient: one operating via health behaviors and the other via psychosocial factors, both having biological intermediates. These hypotheses need not to be competing as one pathway by which psychosocial factors may be related to CHD is through effects on health behaviors. The other is through prolonged overactivity of the stress system. Our research to date supports a model leading from social position through psychosocial and behavioral pathways to pathophysiological changes, subclinical markers of disease, and manifest CHD. The next step will expand the focus beyond working life to social disparities in CHD in aging populations and broaden the conceptual model with alternative pathways, such as health-related selection and genetic vulnerability. Over the last 22 years, a cohort of 10,308 male and female civil servants, now at age 54-79 years, has been followed up with medical examinations at 5-year intervals and with questionnaire surveys every second or third year. Screening for the Phase 9 data collection is underway and, for those unable or unwilling to attend a clinic in central London, we will perform medical examination in the home. With the accumulating data, we are in a unique position to explore causes of the social gradient in CHD after transition to retirement. The specific aims are: (1) to determine whether cumulated exposure to psychosocial, behavioral and biological risk factors during work life explains the greater post-work CHD risk among lower social groups or whether contemporaneous factors, e.g. social isolation and financial insecurity, are more important; (2) to examine whether autonomic, endocrine, metabolic and inflammatory factors underlie the associations of socioeconomic position and the psychosocial environment with CHD in early old age; (3) to determine the extent to which social mobility in adulthood contributes to the post-work CHD gradient; and (4) to examine variants in cardiometabolic genes in order to identify groups of vulnerable people to whom a specific socioeconomic or psychosocial exposure is a particular risk. PUBLIC HEALTH RELEVANCE: Whitehall II's first major achievement was to put the social gradient in health high on the research agenda of the scientific community. Testimonies to the success of that early pioneering work are replica studies in a number of countries and research programs to investigate the pathways from social position to health in every continent. Following recognition by the scientific community, the next hurdle was to bring the social gradient to the attention of policy makers. Here the inspirational effort of Professor Sir Michael Marmot has brought outstanding success culminating in Sir Michael being asked to chair the ongoing WHO Commission on the Social Determinants of Health. Now, twenty years from its inception, Whitehall II is primed to address one of the major challenges of the new millennium; health and health disparities in an ageing population. The wealth of data from midlife places Whitehall II in pole position to elucidate the contribution of inequalities in health and the mechanisms through which they operate in early old age.